Our previous studies concerning the stimulation of cytokine production from human monocytes/macrophages (MO) by the human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein have demonstrated that natural and recombinant preparations of gp120 differ in their ability to cause monokine secretion. Since those recombinant preparations of gp120 that fail to stimulate monokine production are known to bind to CD4, the major receptor for HIV, this suggests that gp120 binding to CD4 on the MO surface may of itself be insufficient to mediate this effect. Data thus far indicate that the ability of HIV-1 gp120 to cause monokine secretion is determined by primary protein structure, as well as post-translational protein modifications such as glycosylation. Whether this also suggests the existence of an alternative receptor to CD4 or a co-receptor necessary for mediating signal transduction is not clear at present. Thus, studies have been initiated to determine what molecules on the surface of human MO bind/interact with the various preparations of HIV gp120.